1. Field of the Invention
The present invention relates generally to the field of drug abuse and addiction therapy. More specifically, the present invention relates to the generation and use of high affinity monoclonal antibodies (MAb) and their derivatives as long acting stimulant antagonists for treating medical problems associated with drug abuse and addiction. In addition, the antigen binding fragments (Fab) and other small molecular fragments of these monoclonal antibodies can serve as a shorter acting stimulant antagonist for treating medical problems like drug overdose.
2. Description of the Related Art
Knowledge gained from basic research into the neurobiology of drug abuse has led to major discoveries in medicine. Nevertheless, the development of medical strategies for treating the complex array of neurological problems associated with drug abuse has been frustratingly slow. In particular, development of medical treatments for alleviating the adverse psychosocial and health effects of d-methamphetamine and similar stimulants is badly needed.
d-Methamphetamine-related hospital emergency cases across the U.S. increased 256% from 1991 to 1994 (Collings, 1996). Toxic effects due to excessive d-methamphetamine use led to more than 10,000 hospital visits each year between 1994 and 1999 and were responsible for more than 2,000 deaths over those same 5 years (Drug Abuse Warning Network, December 2000). The 1995 Toxic Exposure Surveillance System data showed there were 7,601 people treated in health care facilities for amphetamine-like drugs and other stimulants. This is particularly striking since during the same period there were only 3,440 cases of cocaine treatment and a total of 5,170 cases of all types of legal and illegal narcotics (including morphine, codeine and heroin). The current rise in d-methamphetamine use is also alarming because, unlike cocaine, it does not have to be imported. Even an amateur chemist can synthesize this drug in his home using easily obtained reagents and equipment.
Methamphetamine overdose patients can be hyperactive, agitated, and paranoid; and even one-time use of a high dose can lead to a psychotic state lasting several days or weeks. Other complications include hyperthermia, seizures, hypertension, and cardiotoxicity. Recent studies suggest that signs of neurotoxicity (e.g., decreased dopamine transporter density) are present in chronic d-methamphetamine abusers, and these changes appear to correlate with a decrease in cognitive function.
Because there are no specific pharmacological therapies for d-methamphetamine overdose, patients receive palliative and supportive care for symptoms while waiting for the drug to be eliminated by metabolism and renal excretion. Emergency care of patients includes maintenance of ventilation, hydration, electrolyte balance and control of body temperature. Some physicians also choose to administer medications to treat seizures, agitation, or hypertensive crises. Such treatments can aid in managing patients' symptoms, but they do so without removing the causative agent. It would be advantageous to have a medication that could quickly antagonize d-methamphetamine effects by removing the drug from the central nervous system, thereby reversing many of the acute toxicities and reducing the potential for long-term neurological damage.
One reason why clinically effective d-methamphetamine agonists or antagonists have not been discovered is that d-methamphetamine acts at several sites in the central nervous system through multiple mechanisms of action. These mechanisms include, but are not limited to, disruption of vesicular storage of dopamine, inhibition of monoamine oxidase, increased dopamine and serotonin release, and inhibition of dopamine and serotonin reuptake by their respective transporters. In addition, it is likely that any chemical antagonist (or agonist) would share at least some of the adverse effects of d-methamphetamine (e.g., disruption of neurotransmitter homeostasis).
One biologically based approach to treat drug overdose is the use of high-affinity, drug-specific antibodies or Fab fragments. In addition to being relatively safe, except for occasional allergic reactions that can be prevented by the use of humanized monoclonal antibodies, antibody-based therapies act as pharmacokinetic antagonists which gives them several important advantages over treatment with more conventional receptor antagonists. Firstly, there is no receptor antagonist for d-methamphetamine effects at any of its sites of action in the CNS. One of the limitations of development of receptor antagonists is that they will only be capable of attenuating the effects at one type of receptor. Most drugs of abuse have multiple sites of action. Secondly, unlike conventional receptor antagonists (or agonists), antibodies do not inhibit the actions of normal endogenous ligands. In fact, it could be argued that removal of the drug by antibodies might allow for a more normal recovery than treatment with a chemically-derived small molecule competitive agonist or antagonist. Thirdly, since antibodies (and their derivatives like Fab) have extremely high affinities and do not cross the blood-brain barrier, they actually lower drug concentrations throughout the CNS. This allows for a rapid, neuroprotective effect at all sites of action in the CNS.
While monoclonal antibody (mAb) therapy could be a viable approach for antagonizing d-methamphetamine effects, several factors complicate the design of antibody therapy for this drug. First, knowledge of the relationship between antibody affinity and therapeutic efficacy is limited. Previous studies have shown that a single dose of a high-affinity anti-phencyclidine mAb Fab fragment (Kd=1.8 nM) is very effective at reversing a phencyclidine-induced overdose in rats (Valentine et al., 1996; Hardin et al., 1998), and that the intact IgG (Kd=1.3 nM) can produce long-term reductions in brain phencyclidine concentrations (Proksch et al., 2000). While these preclinical data for phencyclidine are impressive, the optimal conditions for achieving such profound effects are not clear. Second, unlike most drugs of abuse, d-methamphetamine (d-METH) has a major active metabolite, d-amphetamine (d-AMP). This metabolite is present at significant concentrations in study rats, and d-AMP area under the concentration-versus-time curves (AUC) constitutes 30% and 26% of the total AUC for d-METH and d-AMP in serum and brain, respectively (Rivière et al., 2000). Thus, pharmacological effects due to d-METH and d-AMP may need to be treated in rats. In humans, however, d-AMP's AUC is <15% of the total serum AUC of d-METH and d-AMP (Cook et al., 1993). Therefore, d-AMP may not contribute as significantly to d-METH's effects in humans.
Thus, the prior art is deficient in the lack of effective means of treating d-methamphetamine overdose and addiction by antibody-based therapy. The present invention fulfills this long-standing need and desire in the art.